Rabies is a major global health issue that kills approximately 40,000 to 70,000 people per year and over 10 million people receive post-exposure prophylaxis (PEP) after exposure to potentially infected animals. Cost and compliance issues have greatly hampered the effectiveness of current vaccines. To confound this issue, current vaccines are not effective at preventing disease from several newly identified rabies related viruses. In addition, live rabies virus (RV) was recently discovered in a lot of vaccine that was supposed to contain inactivated RV. Taken together, the development of novel pre- and post-exposure vaccines is necessary to combat this global health issue. Since pre-exposure vaccination is reserved only for those at-risk populations, such as laboratory workers and veterinarians, PEP is the world-wide standard for human rabies prevention. Current PEPs are comprised of one dose of passive immunization (rabies immune globulin) along with five active immunizations with rabies vaccines. The experiments in this proposal are designed to test the hypothesis that replication-deficient RVs would make excellent rabies PEPs and will require only one to two doses. A hallmark of RV infection that makes PEP feasible is the relatively long period between the time of exposure at the peripheral site and the time when RV infects the central nervous system. As such, a rapid humoral response is absolutely required for a successful PEP. Therefore, the goal of this grant application to identify the most promising vector in small animal models [mice (Aim I) and Syrian hamsters, (Aim II)]. The responses and protection will be compared with animals inoculated with a commercially available inactivated RV vaccine. In summary, the development of a treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of human RV prevention and has the potential to save many lives and reduce costs in both developing and developed countries. In addition, this data will be useful for the development of replication-deficient RV vectors for vaccines against other infectious diseases, such as HIV-1. PUBLIC HEALTH RELEVANCE: The goal of this application is to develop safe and effective alternatives to the current human rabies post- exposure prophylaxis. The development of treatment that relies on only one to two doses of vaccine instead of six inoculations will greatly enhance the effectiveness of rabies virus prevention, save lives and reduce costs in developing and developed countries.